Faculty Bibliography
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673
De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa
Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.
PMID: 41513982
ISSN: 1546-1718
CID: 5981482
Angular Sign of Henle Fiber Layer Hyperreflectivity (ASHH) in Contusion Maculopathy: A Multimodal Imaging Analysis
PURPOSE/OBJECTIVE:To describe the multimodal imaging findings of the angular sign of Henle fiber layer (HFL) hyperreflectivity (ASHH) at baseline and follow-up in patients with contusion maculopathy. METHODS:Eleven eyes of ten patients were captured with multimodal imaging after non-penetrating ocular blunt trauma from a soccer ball, fist, or airsoft pellet. Baseline clinical and imaging characteristics and follow-up outcomes are presented. RESULTS:Hyper-reflective lesions extending along the HFL from the ellipsoid zone (EZ) to the outer plexiform layer consistent with ASHH were identified with optical coherence tomography (OCT). Mean presenting visual acuity (VA) was logMAR 0.59 ± 0.64 (Snellen VA 20/77, range 20/25 to counting fingers) and follow-up visual acuity was logMAR 0.43 ± 0.35 (Snellen VA 20/53, range 20/20 to 20/200). Additional OCT findings included external limiting membrane attenuation and retinal pigment epithelium (RPE) disruption. On follow-up, resolution of ASHH was accompanied by outer nuclear layer thinning with varying degrees of EZ attenuation and RPE loss. A macular hole was detected in one patient on follow-up. CONCLUSION/CONCLUSIONS:ASHH is a distinctive acute OCT feature of contusion maculopathy secondary to blunt injury, causing disruption of the photoreceptors and presumably anterograde alterations in the HFL. Associated RPE alterations may ensue, either acutely or delayed, and are a biomarker of persistent structural abnormalities and variable visual outcomes.
PMID: 40857723
ISSN: 1539-2864
CID: 5910082
Home Optical Coherence Tomography-guided Management of Type 3 Macular Neovascularization
PURPOSE/OBJECTIVE:To explore the impact of home optical coherence tomography (OCT)-guided treatment personalization for type 3 macular neovascularization (MNV) in age-related macular degeneration (AMD). METHODS:A prospective home OCT trial of a patient with a one-month history of type 3 MNV under anti-angiogenic treatment (two "loading" injections). During the 23.4-week study period, the patient's treatment regimen was managed through regular self-imaging, enabling continuous monitoring of retinal fluid dynamics. RESULTS:Over the observation period, the patient performed 143 home OCT measurements (mean 6.1 per week, standard deviation 1), which prompted three in-office visits where three anti-angiogenic injections were delivered at the discretion of the investigator. The mean individualized treatment intervals established through home OCT were 8 weeks, with the patient maintaining stable visual acuity at 20/20 Snellen. Complete resolution of intraretinal fluid was noted between injection. Notably, home OCT revealed unexpected fluctuations in retinal fluid measured as hyporeflective spaces in the absence of treatment. Two out of three injections were administered after the retinal fluid volume had decreased by more than half within two, and eight days following an initial transient spike. CONCLUSION/CONCLUSIONS:The neovascular subtype as defined by the Consensus Nomenclature for Reporting Neovascular AMD Data (CONAN) may serve as a useful management framework when approaching home OCT guided treatment decisions. In type 3 disease, home OCT-guided management demonstrates significant potential for optimizing treatment. Further research is warranted to elucidate the dynamics of retinal fluid variations in different MNV subtypes.
PMID: 40700755
ISSN: 1937-1578
CID: 5901652
Atypical Autofluorescence Findings in Geographic Atrophy: The Influence of Age-Related Choroidal Atrophy
PURPOSE/OBJECTIVE:To describe atypical fundus autofluorescence (FAF) patterns in geographic atrophy (GA) secondary to age-related macular degeneration (AMD) with associated age-related choroidal atrophy (ARCA). METHODS:Multimodal imaging of two cases using (pseudo-)color fundus photography, optical coherence tomography (OCT), fluorescein and indocyanine green angiography, and FAF employed with blue- and green excitation wavelengths on several devices (Spectralis, Heidelberg and (ultra-)widefield [UWF] FAF [California, Optos and EIDON, iCare]). RESULTS:Two female patients, with foveal-involving GA secondary to AMD, were assessed. All eyes demonstrated concurrent features indicative of ARCA on multimodal imaging including a paucity of choroidal vasculature, reduced choroidal pigmentation, macular pigmentary changes, peripapillary atrophy, and subretinal drusenoid deposits. Clinically, progression of GA with coalescence of lobular lesions was observed. Notably, UWF FAF with green-(California) and blue excitation wavelengths (California and EIDON) revealed atypical patterns characterized by isofluorescent FAF signals (indistinguishable from surrounding tissue) or hyperautofluorescent GA lesions. In these cases, blue excitation wavelengths were more effective than green light for delineating GA, owing to increased contrast from hypoautofluorescence related to macular pigment surrounding the lesion. CONCLUSION/CONCLUSIONS:In patients with GA and concomitant ARCA, atypical FAF patterns on UWF imaging complicate the accurate delineation and monitoring of GA. Atypical FAF patterns appear due to the properties of the confocal apertures and postprocessing features of UWF imaging that allow for the detection of scleral autofluorescence in patients with reduced choroidal vasculature, pigment and thickness. In patients with concomitant ARCA, multimodal imaging plays a crucial role in precisely identifying and tracking GA progression.
PMID: 39999827
ISSN: 1937-1578
CID: 5800782
Functional Deficits Associated with Dark Without Pressure
PURPOSE/OBJECTIVE:To describe a patient with progressive visual symptoms and reduced retinal sensitivity corresponding to dark without pressure (DWP). METHODS:Retrospective chart review of a single patient. Comprehensive ophthalmic examinations and multimodal imaging techniques, including optical coherence tomography (OCT), OCT-angiography, and microperimetry, were analyzed. RESULTS:A 23-year-old male presented with progressive peripheral areas of blurred vision superiorly in his right eye and temporally in his left eye. These disturbances corresponded with dark areas of retina inferiorly in his right eye and nasally in his left eye having characteristic features of DWP on multimodal imaging. Although Humphrey visual field (HVF) 24-2 testing was normal, microperimetry showed decreased retinal sensitivity in areas of DWP relative to adjacent areas without DWP. CONCLUSION/CONCLUSIONS:Prior descriptions of DWP have described it as a benign retinal finding showing no functional deficits. We demonstrate that DWP can be associated with progressive visual complaints showing decreased retinal sensitivity on microperimetry and undetected with HVF 24-2 testing.
PMID: 39903922
ISSN: 1937-1578
CID: 5783882
Peripapillary Retinoschisis - The Expanded Spectrum and New Insights from Multimodal Imaging
PURPOSE/OBJECTIVE:To characterize and classify different forms of peripapillary retinoschisis (PPRS), and to clarify the nomenclature of this condition. METHODS:A retrospective, multicenter, multinational case series of PPRS was performed from August 2021 to September 2024. Cases were included if they demonstrated retinoschisis contiguous with and thought to be originating from the optic disc. Demographic and clinical data collected included age, gender, visual acuity, intraocular pressure, axial length, refraction and referring symptoms. Mandatory investigations included optical coherence tomography of the optic disc and macula with radial scans, colour fundus photography, and fundus autofluorescence. Select cases underwent fundus fluorescein and/or indocyanine green angiography. Retinoschisis was characterised by the meridian in relation to the optic disc, layer(s) of the retina affected and associated conditions. A literature review was performed to identify all causes of PPRS. RESULTS:A total of 47 eyes from 41 patients with PPRS were identified, comprising of 22 (54%) females and a mean age of 56 years (range 14-92 years). These were classified into nine aetiologies: Congenital Disc Abnormalities (CDA, n=16 eyes), peripapillary chorioretinal coloboma (n=1), peripapillary atrophy (n=3), glaucoma (n=7), Peripapillary Pachychoroid Syndrome (PPS, n=4), peripapillary choroidal neovascularization (PP-CNV, n=3), high/ pathological myopia (n=5), vitreopapillary traction (VPT, n=4) and idiopathic (n=4). CONCLUSION/CONCLUSIONS:The nine aetiologies of peripapillary retinoschisis can be classified into five groups: non-glaucomatous optic disc abnormalities (CDA, PP-coloboma, PP-atrophy), glaucomatous optic disc abnormalities, peripapillary choroidal diseases (PPS and PP-CNV), vitreous optic disc interface abnormalities and idiopathic. A new entity, "Focal Optic Disc Dome" (FODD) was identified. Understanding the full spectrum of PPRS can assist in correct diagnosis and management.
PMID: 41110675
ISSN: 1879-1891
CID: 5956482
International consensuses and guidelines on central serous chorioretinopathy (CSC) by the Asia Pacific Vitreo-retina Society (APVRS), the Academy of Asia-Pacific Professors of Ophthalmology (AAPPO) and the Academia Retina Internationalis (ARI)
PURPOSE/OBJECTIVE:To establish consensus-based guidelines on the diagnosis, classification, and management of central serous chorioretinopathy (CSC) through a structured expert panel initiated by the Asia-Pacific Vitreo-retina Society (APVRS), the Academy of Asia-Pacific Professors of Ophthalmology (AAPPO), and the Academia Retina Internationalis (ARI), addressing the existing clinical controversies. METHODS:An international panel of 26 experts from 13 countries collaboratively drafted consensus statements spanning five key areas: disease definition, pathophysiology, investigations, current management, and future developments. Consensus was reached through an iterative Delphi process and anonymous voting using a five-point Likert scale. Statements were accepted when >75 % agreement ('agree' & 'strongly agree') was achieved. RESULTS:Consensus was achieved for all 25 statements, reflecting strong alignment among experts. Key agreements included defining CSC as a pachychoroid-driven chorioretinal disorder characterized by neurosensory retinal and/or RPE detachment, with multimodal imaging (optical coherence tomography, fundus autofluorescence, fluorescein angiography, and indocyanine green angiography) recognized as essential for diagnosis. Half-dose photodynamic therapy (PDT) was unanimously endorsed as the first-line treatment for chronic CSC. Oral mineralocorticoid receptor antagonists (MRAs) lacked consensus for therapeutic benefit, aligning with evidence from the VICI and SPECTRA trials. Anti-vascular endothelial growth factor receptor therapy was recommended solely for CSC complicated by a macular neovascularization. Future priorities highlighted standardizing disease classification and exploring targeted therapies through genetic and nanomedicine research. CONCLUSION/CONCLUSIONS:This consensus initiative provides a robust, evidence-based framework for the diagnosis and management of CSC, promoting standardization across clinical practices and guiding future research directions to address persistent gaps in CSC care.
PMID: 41106484
ISSN: 2162-0989
CID: 5955302
Onset of End-Stage Atrophic Age-Related Macular Degeneration as an End Point-A Delphi Study: Classification of Atrophy Meetings Report 7
PURPOSE/UNASSIGNED:To investigate whether consensus can be reached on the acceptability of end-stage atrophy onset as a clinical end point in early intervention trials of age-related macular degeneration (AMD), and the criteria for defining such an end point. DESIGN/UNASSIGNED:A modified Delphi study. PARTICIPANTS/UNASSIGNED:International panel of experts in AMD, retinal imaging, and histopathology that are part of the Classification of Atrophy Meetings group. METHODS/UNASSIGNED:A modified Delphi study was undertaken to determine if there is consensus on the acceptability of the onset of end-stage atrophic AMD as a clinical end point to evaluate early interventions and the criteria for defining such an end point. Two initial rounds of online surveys were conducted. Aggregate results and anonymized comments were provided after each round, followed by a face-to-face meeting before a final survey round was completed. MAIN OUTCOME MEASURES/UNASSIGNED:Statements where consensus was reached, defined as ≥80% of responses within the 3-point bracket for agreement or disagreement based on a 9-point Likert rating scale, from a total of 33 statements included in the final round of the survey. RESULTS/UNASSIGNED:Consensus was reached for the statement that the onset of end-stage atrophic AMD was an appropriate clinical end point to evaluate early interventions (82% responses in agreement). Consensus was also reached for the statement that such an end point should be defined based on anatomical changes that have been previously shown in clinical studies to be associated with marked, but not necessarily complete, functional loss (95% responses in agreement). Consensus was nearly reached for the specific criterion that ≥90% of such atrophic AMD lesions should have ≥1 test location that was ≤10 decibels on 2 microperimetry tests (77% responses in agreement). CONCLUSIONS/UNASSIGNED:There was expert group consensus that the onset of end-stage atrophy is an appropriate clinical end point to evaluate early interventions in AMD, and that such an end point should show evidence of marked functional loss in prior clinical studies. We believe these findings will help to define incident clinical end points that are acceptable to regulatory authorities. FINANCIAL DISCLOSURES/UNASSIGNED:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PMCID:12133686
PMID: 40469898
ISSN: 2666-9145
CID: 5930732
Re: Monés et al: Spontaneous soft drusen regression without atrophy and the drusen ooze (Ophthalmology Retina 2025;9:828-837) [Letter]
PMID: 40905894
ISSN: 2468-6530
CID: 5930892
Evidence and Consensus-based Imaging Classification Criteria in Multiple Evanescent White Dot Syndrome - Multimodal imaging in Uveitis (MUV) Taskforce Report 6
PURPOSE/OBJECTIVE:To develop imaging and consensus-based guidelines on the application of multimodal imaging in multiple evanescent white dot syndrome (MEWDS). DESIGN/METHODS:Consensus agreement guided by literature, and an expert committee using a nominal group technique (NGT). METHODS:The expert committee employed a structured NGT with multiple rounds of discussion, conflict resolution, and anonymous voting to: (1) establish imaging criteria for diagnosing and monitoring MEWDS using color fundus photography (CFP), optical coherence tomography (OCT), fundus autofluorescence (FAF), fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and OCT angiography (OCTA); and (2) develop consensus-based recommendations for assessing specific characteristics in patients with MEWDS. These formal recommendations were derived from a structured NGT using illustrative cases of MEWDS and were further voted upon by the entire task force. RESULTS:The diagnosis of acute MEWDS is supported by distinct multimodal features on CFP, multi-focal disruption of the ellipsoid/interdigitation zone with overlying outer retinal hyper-reflectivity with OCT, and hyper-autofluorescent spots with FAF (short-wave blue/green). In complex cases, wreath-like lesions on FFA and the absence of early hypofluorescence on ICGA help differentiate MEWDS from other chorioretinopathies. The lack of specific choroidal changes on OCT and preserved signal on OCTA on retinal and inner choroidal slabs also aid in diagnosis. CONCLUSIONS:Multimodal imaging is essential for diagnosing MEWDS and differentiating it from other non-infectious uveitis types, extending the Standardization of Uveitis Nomenclature (SUN) classification. These imaging criteria enable detailed assessment of disease activity and offer valuable insights into MEWDS pathogenesis.
PMID: 40571046
ISSN: 1879-1891
CID: 5874582
